PROJECT SUMMARY The enclosed career development award is designed to prepare Stephanie Markovina, MD, PhD to transition to independence as a physician scientist studying tumor cell death and survival in response to ionizing radiation. Dr. Markovina graduated with honors in Biology from Washington University, then obtained her medical and graduate degrees through the University of Wisconsin's Medical Scientist Training Program. After finishing clinical residency in radiation oncology, she joined the faculty at Washington University, and has become embedded in Dr. Gary Silverman's laboratory. She has demonstrated that SERPINB3, a member of the serine protease inhibitor superfamily, mediates resistance to radiation in cervical cancer cells. She proposes to investigate the mechanism of this cytoprotection and test the hypothesis that SERPINB3 prevents lysosome-mediated cell death following IR as an innate and/or acquired defense mechanism. Washington University School of Medicine is the ideal setting for Dr. Markovina to develop the remaining skills necessary to transition to independence and to answer these critical questions. Expertise within the Radiation Oncology Department and campus wide, as well as robust research resources facilitate a collaborative environment that has produced some of the most impactful biomedical research. Dr. Silverman discovered the SERPINB3 locus, and has since characterized various important functions of the intracellular serpins in human physiology and disease, and their role in regulation of cell death mechanisms. Thus, this expertise along with his track record of training young scientists make Dr. Silverman an ideal mentor for this proposal. Dr. Markovina will take graduate level courses, present her work locally and at international meetings, and work closely with Dr. Silverman and his group in order to develop key knowledge and technical skills in cell death mechanisms, imaging techniques and animal tumor models. Dr. Markovina has dedicated her early professional career to cancer research and navigated a unique path through radiation oncology to become one of the few physician scientists in the field. She has found that knock-out of SERPINB3 in cervix cancer cells results in a lower proliferation rate, and renders cells significantly more sensitive to IR and to lysosome mediated necrosis in response to severe cell stress. Through the proposed research she will 1) determine the mechanism of SERPINB3 cytoprotection against IR, 2) test the hypothesis that SERPINB3 regulates IR-induced tumor cell death by targeting lysosomal cathepsins, and 3) determine whether SERPINB3 functions as an oncoprotein promoting tumor growth, metastasis and survival in the face of radiation treatment. Dr. Markovina's overall goal is to better understand mechanisms of cell death and survival in cancer cells in response to ionizing radiation, which is critical to developing improved therapies. Her motivation is not only her own patients undergoing radiation therapy for cervical cancer, but the roughly two-thirds of all patients with cancer who will receive radiation as part of their cancer management.